DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is a growing contributor to advanced kidney disease and mortality among Veterans. Strategies are needed to reduce disease progression following AKI. The goals of this proposal are to identify modifiable risk factors to avert long-term loss of kidney function following AKI and testable care strategies that may reduce these risks. Renal recovery after AKI is poorly understood. Patterns of recovery vary and can be lengthy. Recurrent AKI is a common source of morbidity and mortality among elderly AKI survivors and can also complicate recovery. Determining the clinical significance of recovery and recurrent AKI among Veteran AKI survivors will bridge knowledge gaps in understanding the progression from AKI to ESRD and improve risk stratification. Improving outcomes following AKI requires identifying testable care strategies. Identifying these strategies requires better understanding of the care delivered following AKI and its association with patient outcomes. The use of inhibitors of the renin-angiotensin-aldosterone system inhibitors (RAASi) is the cornerstone of treating conditions highly prevalent in patients with AKI (e.g. chronic kidney disease, diabetes, cardiovascular disease, and hypertension). However, the use of this therapy has recently been questioned in certain patients (e.g. the elderly) or when applied aggressively (i.e. combination therapy). A critical aspect of RAASi use is balancing the benefits with its known ability to hamper autoregulation, an adaptive response that protects against AKI. AKI also impairs autoregulation. Therefore, determining the potential risks of RAASi use in AKI survivors is essential and may challenge current treatment paradigms. We will perform a series of studies within a National cohort of Veteran AKI survivors to characterize variations in the patterns of recovery, recurrent AKI, and their association with future ESRD. We will also identify clinical predictors of recovery and recurrent AKI that can improve risk stratification for AKI survivors. We will then examine how AKI impacts the delivery of specific care strategies, focusing on RAASi therapy. We will characterize different patterns of RAASi use among AKI survivors, identify the clinical features that associate with RAASi use, and examine the potential association between RAASi use and recurrent AKI. These findings will help identify testable care strategies and inform individual risk/benefit assessments. In addition, the characterization of risks and benefits, methodological refinements, and quantification of potential effect sizes will set the stage for future studies needed to improve outcomes in AKI survivors. The proposed studies will be performed in a retrospective National VA data cohort of hospitalized patients between 2005 and 2014. All adult (age=18) patients with AKI, defined using changes in serum creatinine in accordance with consensus criteria will be eligible. The assembly of the cohort will leverage the VA Informatics and Computing Infrastructure (VINCI), which encompasses a national electronic data warehouse pooling data from all VA hospitals and the VA Information Resource Center (VIREC), providing Center for Medicare Services (CMS) data intersected with the electronic medical records of Veterans. VINCI will provide the majority of the observations required to build our Aims and is already linked to VIREC data. The CMS data in VIREC will be linked to VINCI observations to ensure capture of the outcome of ESRD or dialysis via cross- linkage with the United States Renal Data Systems (USRDS).

Preventing disease progression is a vital part of the federal response to kidney disease. Acute kidney injury (AKI) is a growing contributor to advanced kidney disease and mortality among Veterans. Reducing these outcomes will require developing optimal care strategies for AKI survivors. These strategies will depend on understanding how kidney function recovers following AKI, identifying risk factors for recurrent AKI, and identifying care patterns that associate with poor outcomes. The revised proposal will investigate recovery and recurrent AKI as modifiable risk factors for future ESRD. In addition, we will characterize variations in the application of specific therapies, including inhibitors of the renin-angiotensin-aldosterone axis (RAASi), and their association with recurrent AKI. The findings will improve knowledge of the transition between AKI and ESRD, how AKI impacts the delivery of care, inform current clinical decision-making, and provide the framework for future clinical studies needed to reduce the dismal outcomes of this disease.